Preparation of α-fluoroketones

ABSTRACT

The use of polar organic solvent as the solvent in the direct fluorination, to make an α-fluoroketone, of an enol ester or enol trialkylsilyl ether of a compound containing a tautomerisable ketone group, the solvent being relatively inert to fluorine and one in which the enol ester or enol trialkylsilyl ether is relatively stable to hydrolysis. Preferably the solvent is anhydrous, e.g. anhydrous acetonitrile. Alternatively commercial formic acid containing 3% water may be used with a said enol ester.

This invention relates to the preparation of α-fluoroketones.

α-Fluoroketones are valuable compounds, both as intermediates in thepreparation of biologically active molecules and as biologically activemolecules in their own right. There is no satisfactory direct method ofreplacing the α-hydrogen of a ketone by fluorine, but by first making anenol ester or a trialkylsilyl ether of the parent ketone, and thentreating either of these with an electrophilic fluorinating agent, goodyields of α-fluoroketone can be obtained.

Examples of published attempts to prepare α-fluoroketones include thefollowing:

1. The treatments of enol esters with reagents such as:

a) CF₃ COF/CF₃ CF₂ OF (S Rozen and Y Menachem, J Fluorine Chem. 1980,16, 19)

b) N-fluoropyridinium pyridine heptafluorodiborate (A J Poss, M Van DerPuy, D Nalewajek, G A Shia, W J Wagner and R L Frenett; J Org Chem,1991, 56, 5962)

c) xenon difluoride, caesium fluoroxysulphate (S Stavber, B Sket, B Zajcand M Zupan; Tetrahedron, 1989, 45, 6003)

d) 1-(chloromethyl)4-fluoro-1,4-diazabicyclo[2,2,2]octane bis(tetrafluoroborate) (G S Lal; J Org Chem, 1993, 58, 2791)

2. The treatments of silyl ethers with reagents such as:

a) xenon difluoride (G L Cantrell and R Filler; J Fluorine Chem, 1985,27, 35 and T Tsushima, K Kawada and T Tsuji; Tetrahedron Letters, 1982,23, 1165)

b) CF₃ OF (W J Middleton and E M Bingham, J Am Chem Soc, 1980, 102,4846)

c) N-fluorobenzenesulphonimide (E Differding and H Ofner, Synlett, 1991,187)

d) 1-(chloromethyl)4-fluoro-1,4-diazabicyclo[2,2,2]octanebis(tetrafluoroborate) (G S Lal; J Org Chem, 1993, 58, 2791)

e) N-fluoropyridinium salts (T Umemoto, S Fukami, G Tomizawa, KHarasawa, K Kawada and K Tomita; J Am Chem Soc, 1990, 112, 8563).

These electrophilic fluorinating agents are often difficult to prepareand sometimes difficult to handle, or they are expensive to obtain. Theuse of elemental fluorine for such fluorinations would seem to affordcertain advantages. When enol acetates have been treated with fluorinein the past. "no matter how mild the conditions used the reactionresulted in a very complicated mixture and no α-fluoroketones could bedetected". (S Rozen and Y Menachem: J Fluorine Chem 1980, 16, 19).

The use of elemental fluorine for the fluorination of trialkylsilylethers has been attempted by G L Cantrell and R Filler (J Fluorine Chem,1985, 27, 35) and by S Purrington, N V Lazaridis and C L Bumgardner(Tetrahedron Letters, 1986, 27, 2715). Cantrell et al found that when adichloromethane solution of the trimethylsilylenol ether ofcyclohexanone was treated with elemental fluorine, only cyclohexanonewas obtained. Purrington et al was successful in obtainingα-fluoroketones but their reactions were carried out at -78° C. and thesolvent was chlorotrifluoromethane. Accordingly the reactions werecarried out at a temperature which is expensive to maintain and in asolvent which has been banned under the terms of the Montreal Protocolon the use of chlorofluorocarbons.

Surprisingly we have now found that enol esters and trimethylsilylethers of ketones can be treated with elemental fluorine at ambienttemperatures in convenient, available solvents to give α-fluoroketonesin good yields. In one aspect this invention is the use of a polarorganic solvent in the direct fluorination, to make an α-fluoroketone,of an enol ester or enol trialkylsilyl ether of a compound containing atautomerisable ketone group, the solvent being relatively inert tofluorine and one in which the selected ester or ether is relativelystable to hydrolysis. Enol esters are preferred over trialkylsilylethers.

According to the present invention there is more particularly provided aprocess for the preparation of an α-fluoroketone of formula R--CHFC=O.R'which includes the steps of converting a ketone of formula R--CH₂ C=O.R'into a ketone derivative which is an enol ester of formulaR--CH=C(OCO.R")R' or is a trialkylsilyl ether of formulaR--CH=C(OSiR"₃).R', followed by the reaction of that ketone derivative,dissolved in a polar organic solvent which is relatively inert towardsfluorine and in which the ketone derivative is relatively stable tohydrolysis, with elemental fluorine. The essence of the substrate,however, is that it is a compound containing an enol ester or enoltrialkylsilylether of a tautomerisable ketone function and, except forthe double bond of the enol group, relatively resistant to fluorination.

In the above formulae, the groups R and R' are independently selectedfrom alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryland substituted aryl, said groups R and R' being optionally joined toone another to form a cyclic structure such as a steroid, an examplebeing the enol acetate derived from a cholestanone, especially5α-cholestan-3-one.

Suitable substituents include another of the R/R' groups; for example,alkyl may be substitued by cycloalkyl or aryl or aryl substituted byalkyl. Also suitable are halogen (e.g. chlorine or fluorine), alkoxy andaryloxy, as well as other groups which are relatively inert to fluorine.Any of the aforegoing substituents may be substituted in turn by one ormore other suitable substituents, to form groups such as, for example,haloalkoxy or alkoxyaryl. The group R" is alkyl or cycloalkyl.Preferably R and R' contain up to 10 carbon atoms. Preferably, R" hasfrom 1 to 4 carbon atoms.

The conversion of the ketone into the enol ester or the trialkylsilylether may be carried out by any of the methods known to those familiarwith the art. For example, the enol acetate (R" is CH₃) may be made bytreating the parent ketone with acetic anhydride and acetic acid, orwith isopropenyl acetate in the presence of a catalyst such as p-toluenesulphonic acid. The conversion of the ketone into the trialkylsilylether, may be carried out by methods such as those described by H OHouse, L J Czuba, M Gall and H D Olmstead; J Org Chem 1969, 34, 2324, orD T W Chu and S N Huckin; Canad J Chem, 1980,58, 138 and referencescited therein.

The fluorination step may be carried out by contacting fluorine gas,normally diluted with an inert gas such as nitrogen or argon, with asolution of the enol ester or trialkysilyl ether in a polar organicsolvent which is relatively inert towards fluorine.

Preferably the solvent should have high polarity, for example a polaritysimilar to acetonitrile or formic acid. In one class of processes thepolar solvent is not dry but, nonetheless, the ketone derivative (etheror ester) is relatively stable to hydrolysis in it; for example,commercially available formic acid contains 2-3% water, which watercauses significant hydrolysis of trialkylsilyl ethers of ketones but notof their enol esters.

The solvent is not only one in which the substrate (i.e. ketonederivative) remains relatively stable to hydrolysis but is alsorelatively inert towards fluorine. That is to say, a majority of thefluorine in the reaction mixture reacts with the substrate rather thanwith the solvent and a majority of the substrate reacts with fluorinerather than with water. Of course, if the solvent is substantiallyanhydrous then the question of hydrolysis does not arise.

In one class of embodiments, the solvent is an alkane nitrile,especially acetonitrile or, less preferably, propionitrile. In anotherclass of embodiments, the solvent is an alkanoic acid, especially formicacid. The invention does not exclude other solvent compounds or mixturesalthough the skilled reader will be aware that a solvent is a substancewhich does not react significantly with the reagents.

The reaction may be carried out by passing the fluorine gas (usuallydiluted) through a stirred solution of the enol ester or trialkysilylether or a stream of a solution of these substrates may be contactedwith the fluorine gas in a concurrent or countercurrent manner.

The fluorination process may be carried out at a temperature of from-45° C. to +80° C. Preferably, it is carried out at a temperature offrom -20° C. to +30° C. The concentration of fluorine is preferably from1% to 50% by volume, more preferably from 2% to 25% by volume and mostpreferably from 5% to 15% by volume.

The ratio of fluorine to enol ester (or trialkysilyl ether) may bevaried within wide limits although it is preferred that the molar ratioof fluorine to substrate is from 0.5:1 to 6:1 and more preferably from0.8:1 to 3:1. The use of a higher ratio of fluorine to substrate ensuresthat all of the substrate is converted into the α-fluoroketone.

After the fluorination reaction has been performed, the end product maybe hydrolysed to convert the substituted enol function to a ketone. Moreparticularly, when the fluorination reaction is complete, the productsmay be isolated by purging the system with inert gas. This may befollowed by contacting the reaction mixture with water or a dilutemineral acid. The α-fluoroketone may then be extracted from the aqueousmixture with a suitable organic solvent such as dichloromethane. Theproduct may then be isolated by removing the solvent from the extractsby distillation followed by an appropriate purification of the residuesuch as by distillation, chromatography, recrystallisation or acombination of these procedures.

Thus, the α-fluoroketone is usually recovered from the reaction mixtureas part of the fluorination process. It may be subjected to one or morefurther process to make a subsequent end product, or alternatively,formulated into a preparation.

The invention includes a process for the preparation of anα-fluoroketone, comprising directly fluorinating, to make anα-fluoroketone, an enol ester or enol trialkylsilyl ether of a compoundcontaining a tautomerisable ketone group, the ester or ether being in apolar organic solvent which is relatively inert to fluorine and one inwhich the enol ester or enol trialkylsilyl ether is relatively stable tohydrolysis.

Embodiments of the present invention will now be described, by way ofexample only.

EXAMPLE 1

Through a stirred solution of 1-cyclohexenyl acetate (3.5 gm, 25 mmol)in dry acetonitrile (50 ml) was bubbled fluorine (50 mmol diluted to 10%v/v with nitrogen) over 110 mins. The reaction temperature wasmaintained at about 0° C. by cooling the reaction vessel externally.When the reaction was complete, the fluorine was switched off and thevessel was purged with nitrogen. The reaction mixture was then pouredinto water and thoroughly shaken before being extracted withdichloromethane. Most of the solvent was removed from the dried extractsunder reduced pressure using a rotary evaporator. The residue was thendistilled under reduced pressure using a short path distillationapparatus to give a main fraction (2.3 gm) which contained one majorcomponent (77% of total area of chromatogram) and several minor ones. Asample of the main component was isolated by preparative scale gaschromatography and identified as 2-fluorocyclohexanone (¹⁹ F NMR δ-188.7ppm, d, J_(HF) 48.7 Hz. ¹ H NMR δ 4.96 ppm, dq, J_(HF) 49 Hz, J_(HH) 5.9Hz, Multiplets at 2.6, 2.4, 2.1 and 1.7 ppm, M+ 116). Yield of2-fluorocyclohexanone=61%.

EXAMPLE 2

Through a stirred solution of 1-(trimethylsiloxyl)-cyclohexene (3.4 gm,20 mmol) in dry acetonitrile (50 ml) was bubbled fluorine (60 mmoldiluted to 10% v/v with nitrogen) over 180 mins. The reactiontemperature was maintained at about 0° C. by cooling the reaction vesselexternally. When the reaction was complete, the fluorine was switchedoff and the vessel was purged with nitrogen. The reaction mixture wasthen poured into water and thoroughly shaken before being extracted withdichloromethane. Most of the solvent was removed from the dried extractsunder reduced pressure using a rotary evaporator. The residue was thendistilled under reduced pressure using a short path distillationapparatus to give a mixture of solvent (46%), cyclohexanone (2%),2-fluorocyclohexanone (42%) and some minor components. Cyclohexanone and2-fluorocyclohexanone were identified by gc/ms and in the case of thefluoro-compound, also by its 19_(F) NMR spectrum. Yield of2-fluorocyclohexanone=45%.

EXAMPLE 3

In a similar manner to that outlined in Example 1, 20 mmol of1-cyclooctenyl acetate dissolved in acetonitrile was treated with 50mmol fluorine over 110 min. On work up, the main product was identifiedas 2-fluorocyclooctanone (HRMS; Found, 144.0950; C₈ H₁₃ FO requires144.0950; δ_(F) 191.6 (m); δ_(H) 1.36-2.7 (m, 12 H), 4.9 (dm, J,_(H),F49.5, 1 H); δ_(C) 20.5 (d, ³ J_(C),F 3.6, C4), 24.6 (d, ³ J_(C),F 3.7,C8), 24.7 (s), 27.2 (s), 32.7 (d, ² J_(C),F 21, C3), 39.6 (s), 91.5 (d,¹ J_(C),F 184.7 C2), 213.9 (d, ² J_(C),F 20.9, C1); m/z 144 (M+, 3%) 55(100)). Yield of 2-fluorocyclooctanone=66%.

EXAMPLE 4

In a similar manner to that outlined in Example 3, 20 mmol of4-nonenyl-5-acetate was treated with 50 mmol fluorine over 110 min. Onwork up, the main product was identified as 4-fluoro-5-nonanone (HRMS;Found,160.1263; C₉ H₁₇ FO requires 160.1263; δF-193 (m); δH 0.94 (m, 6H), 1.2-1.9 (m, 8 H), 4.7 (ddd, J_(H),F 49.5, J_(H),F 6, J_(H),F 6, 1H); δc 13.6 (s, CH₃), 13.8 (s,CH₃), 17.9 (s), 22.3 (s), 24.7 (s), 34 (d,² J_(C),F 20.5, CHF.CH₂), 37.7 (s, CH₂ CO), 95.9 (d, ¹ J_(C),F 182.5,CHF), 210.5 (d, ² J_(C),F 24.1, CO), m/z 160 (M+, 6%), 57 (100). Yieldof 4-fluoro-5-nonanone=61%.

EXAMPLE 5

In a similar manner to that outlined in Example 3, 20 mmol of4-tert-butyl-1-cyclohexenyl acetate was treated with 50 mmol fluorineover 110 min. On work up, the main product was identified as a mixtureof cis and trans 2-fluoro-tert-butyl cyclohexanone (δF-186 (tm) (trans),188.7 (dm) (cis). GC/MS showed two compounds, having significantlydifferent retention times. m/z 172. The literature (N. L. Allinger andH. M. Blatter; J. Org. Chem., 1962. 27. 1523, S. Rozen and Menahem, J.Fluorine Chem., 1980, 16, 19; B. Zajc and M. Zupan, J. Org. Chem., 1982,47. 573.) suggests that the compound with the shorter retention time istrans 2-fluoro-4-tert-butyl cyclohexanone and the other is the cisisomer). Yield cis and trans 2-fluoro-4-tert-butyl cyclohexanone=45%.

EXAMPLE 6

In a similar manner to that outlined in Example 2, 20 mmol of1-(trimethylsiloxy)-cyclooctene was treated with 50 mmol fluorine over110 min. On work up, the main product was identified as2-fluorocyclooctanone. Yield=23%.

EXAMPLE 7

In a similar manner to that outlined in Example 6, 20 mmol of5-(trimethylsiloxy) 4-nonene was treated with 50 mmol fluorine over 110min. On work up, the main product was identified as 4-fluoro-5-nonanone.Yield=35%.

EXAMPLE 8

In a similar manner to that outlined in Example 1, 20 mmol of2-cyclohexenyl acetate dissolved in 50 ml formic acid was treated with64 mmol fluorine over 240 min. On work up, the main product wasidentified as 2-fluorocyclohexanone. Yield=71%.

EXAMPLE 9

In a similar manner to that outlined in Example 8, 20 mmol of1-cyclooctenyl acetate dissolved in 50 ml formic acid was treated with64 mmol fluorine over 240 min. On work up, the main product wasidentified as 2-fluorocyclooctanone. Yield=61%.

EXAMPLE 10

In a similar manner to that outlined in Example 8, 20 mmol of4-tert-butyl-1-cyclohexenyl acetate dissolved in 50 ml formic acid wastreated with 64 mmol fluorine over 240 min. On work up, the main productwas identified as a mixture of cis and trans 2-fluoro-4-tert-butylcyclohexanone. Yield=46%.

EXAMPLE 11

In a similar manner to that outlined in Example 8, 20 mmol of4-nonenyl-5-acetate dissolved in 50 ml formic acid was treated with 64mmol fluorine over 240 min. On work up, the main product was identifiedas 4-fluoro-5-nonanone. Yield=71%.

We claim:
 1. A process for the preparation of an α-fluoroketone which comprises fluorinating with elemental fluroine an enol compound selected from the group consisting of enol esters and enol trialkylsilyl ethers of, in either case, compounds containing a tautomerisable ketone group, the enol compound being dissolved in a polar organic solvent which is relatively inert to fluorine and in which the enol compound is relatively stable to hydrolysis.
 2. A process according to claim 1 wherein the elemental fluorine is fluorine gas diluted with an inert gas.
 3. A process according to claim 2 wherein the inert gas is nitrogen or argon.
 4. A process according to claim 2 wherein the fluorine gas is present in the inert gas/fluorine mixture in an amount of from 1% to 50% by volume.
 5. A process according to claim 3 wherein the fluorine gas is present in the mixture in an amount of from 5% to 15% by volume.
 6. A process according to claim 1 wherein the solvent has a high polarity.
 7. A process according to claim 1 wherein the solvent has a polarity of which formic acid or acetonitrile is representative.
 8. A process according to claim 1 wherein the solvent is an alkane nitrile containing up to four carbon atoms or an alkanoic acid containing up to four carbon atoms.
 9. A process according to claim 1 wherein the solvent is acetonitrile.
 10. A process according to claim 1 wherein the solvent is formic acid.
 11. A process according to claim 1 wherein the solvent is substantially anhydrous.
 12. A process according to claim 11 wherein the solvent is acetonitrile or formic acid.
 13. A process according to claim 1 wherein the solvent contains a small amount of water, and the enol compound is a said enol ester.
 14. A process according to claim 13 wherein the solvent is formic acid.
 15. A process according to claim 1 which is carried out at a temperature of from -45° C. to +80° C.
 16. A process according to claim 8 which is carried out at a temperature of from -20° C. to +30° C.
 17. A process according to claim 2 wherein the molar ratio of fluorine to the enol compound is from 0.5:1 to 6:1 and the solvent is acetonitrile or formic acid.
 18. A process according to claim 1 wherein, when the fluorination reaction is complete, the reaction mixture is contacted with water or a dilute mineral acid to convert the enol function to a ketone.
 19. A process according to claim 1 wherein the enol compound is of the formula R--CHFC=O. R' wherein R and R' are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl, said substituents being another R/R' group, halogen, alkoxy or aryloxy, or wherein groups R and R' together form a cyclic structure, and R" is alkyl or cycloalkyl, said enol ester being of the formula R--CH=C(OCO.R")R' and said trialkylsilyl ether being of the formula R--CH=C(OSiR"₃).R'.
 20. A process according to claim 19 wherein the solvent has a polarity of which formic acid or acetonitrile is representative, the elemental fluorine is fluorine gas diluted with an inert gas, and the process is carried out at a temperature of from -45° C. to +80° C.
 21. A process for the preparation of an α-fluoroketone which comprises fluorinating with elemental fluorine an enol compound selected from the group consisting of enol esters and enol trialkylsilyl ethers of, in either case, compounds containing a tautomerisable ketone group, the enol compound being dissolved in a polar organic solvent which is an alkane nitrile containing up to four carbon atoms or an alkanoic acid containing up to four carbon atoms, provided that the solvent is anhydrous or, alternatively, that the solvent contains a small amount of water and the enol compound is a said enol ester atoms, provided that the solvent is anhydrous or, alternatively, that the solvent contains a small amount of water and the enol compound is a said enol ester.
 22. A process according to claim 21 wherein the elemental fluorine is fluorine gas diluted with an inert gas, the solvent is acetonitrile or formic acid and said small amount of water is not more than 3%.
 23. A process according to claim 21 wherein the enol compound is of the formula R--CHFC=O.R' wherein R and R' are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl, said substituents being another said R/R' group, halogen, alkoxy or aryloxy, or wherein groups R and R' together form a cyclic structure, and R" is alkyl or cycloalkyl, said enol ester being of the formula R--CH=C(OCO.R")R' and said trialkylsilyl ether being of the formula R--CH=C(OSiR"₃).R'.
 24. A process according to claim 23 wherein the solvent is acetonitrile, R and R' contain up to 10 carbon atoms, and R" has from 1 to 4 carbon atoms.
 25. A process for the preparation of an α-fluoroketone of formula R--CHFC=O.R' which includes the steps of converting a ketone of formula R--CH₂ C=O.R' into a ketone derivative which is an enol ester of formula R--CH=C(OCO.R")R' or is a trialkylsilyl ether of formula R--CH=C(OSiR"₃).R', followed by the reaction of that ketone derivative, dissolved in a polar organic solvent which is relatively inert towards fluorine and in which the ketone derivative is relatively stable to hydrolysis, with elemental fluorine, the groups R and R' being independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl, said groups R and R' being optionally joined to one another to form a cyclic structure, and the group R" being alkyl or cycloalkyl.
 26. A process according to claim 25 wherein R and R' contain up to 10 carbon atoms and R" has from 1 to 4 carbon atoms.
 27. A process according to claim 25 wherein R and R' are independently selected from alkyl, cycloalkyl and aryl, said groups R and R' being optionally joined to one another to form a cyclic structure.
 28. A process according to claim 25 wherein the elemental fluorine is fluorine gas diluted with an inert gas.
 29. A process according to claim 25 wherein the solvent has a high polarity.
 30. A process according to claim 25 wherein the solvent is acetonitrile.
 31. A process according to claim 25 wherein the solvent is formic acid.
 32. A process according to claim 25 wherein the solvent is substantially anhydrous.
 33. A process according to claim 32 wherein the solvent is formic acid.
 34. A process according to claim 25 wherein the solvent contains a small amount of water, and the ketone derivative is a said enol ester.
 35. A process according to claim 34 wherein the solvent is formic acid and the small amount of water is up to 3% water.
 36. A process according to claim 25 wherein the process is carried out at a temperature of from -45° C. to +80° C. and the molar ratio of fluorine to enol ester or trialkylsilyl ether is from 0.5:1 to 6:1.
 37. A process for the preparation of an α-fluoroketone of formula R--CHFC=O.R' comprising:converting a ketone of formula R--CH₂ C=O.R into a ketone derivative which is an enol ester of formula R--CH=C(OCO.R")R' or is a trialkylsilyl ether of formula R--CH=C(OSiR"₃).R' wherein R and R' are independently selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl, said substituents being another said R/R' group, halogen, alkoxy or aryloxy, or wherein groups R and R' together form a cyclic structure, and R" is alkyl or cycloalkyl; and reacting that ketone derivative, dissolved in acetonitrile or formic acid, with elemental fluorine.
 38. A process according to claim 37 wherein R and R' contain up to 10 carbon atoms, R" has from 1 to 4 carbon atoms, and the elemental fluorine is fluorine gas diluted with an inert gas. 